Shojaati Kushiar, Causevic Maja, Kadereit Bert, Dick Bernhard, Imobersteg Jeanine, Schneider Henning, Beinder Ernst, Kashiwagi Maki, Frey Brigitte M, Frey Felix J, Mohaupt Markus G
Division of Nephrology/Hypertension, University of Berne, Berne, Switzerland.
Kidney Int. 2004 Dec;66(6):2322-8. doi: 10.1111/j.1523-1755.2004.66031.x.
In normal pregnancy, an increased aldosterone (Aldo) concentration coincides with volume expansion. In preeclampsia, Aldo levels are low despite intravascular volume depletion. The present investigation aimed to characterize the compromised Aldo synthesis in preeclampsia, and to identify the molecular basis hereof.
We recruited 66 pregnant women (24 uneventful, 42 preeclamptic). Genomic DNA was isolated from peripheral blood leukocytes. Urine samples were obtained for gas chromatography-mass spectroscopic measurements of steroid hormones reflecting apparent Aldo synthase (CYP11B2) and 11-hydroxylase (CYP11B1) activities. Polymerase chain reaction (PCR)-based screening for CYP11B2 mutations was performed by SSCP, restriction analysis, and sequencing.
CYP11B1 activity was unaltered, but reduction of mean tetrahydro (TH)-Aldo excretion by a factor of 3.9 indicated a diminished CYP11B2 activity in preeclampsia. Accordingly, the ratios of (TH-11-dehydrocorticosterone [A]+TH-corticosterone [B]+5alpha-THB) to (TH-cortisone +TH-cortisol [F]+5alpha-THF) and of 18-OH-THA to THAldo were increased in preeclampsia 2.6- and 15.2-fold, respectively, indicating reduced Aldo synthesis due to diminished methyl oxidase (MO) activity. A lower percentage of women with normal pregnancies had CYP11B2 mutations when compared to preeclamptic women (P < 0.05). Eight polymorphisms were detected, two of which were non-amino acid conserving. Of those, the mutation V386A, earlier found to jeopardize MO activity, was exclusively observed in preeclampsia (0% vs. 17%; P < 0.05).
Aldo deficiency due to a compromised MO step of Aldo synthesis favors extracellular volume depletion, and may account for an increased risk of placental hypoperfusion and consecutive development of preeclampsia. The sole presence of mutation V386A in preeclamptic mothers may identify a subgroup with an increased risk to develop preeclampsia during pregnancy.
在正常妊娠中，醛固酮（Aldo）浓度升高与血容量增加同时出现。在子痫前期，尽管血管内容量减少，但醛固酮水平却较低。本研究旨在描述子痫前期醛固酮合成受损的特征，并确定其分子基础。
我们招募了66名孕妇（24名正常妊娠，42名子痫前期患者）。从外周血白细胞中分离基因组DNA。采集尿液样本，通过气相色谱 - 质谱法测量反映醛固酮合酶（CYP11B2）和11β - 羟化酶（CYP11B1）活性的类固醇激素。通过单链构象多态性分析（SSCP）、限制性分析和测序，对CYP11B2突变进行基于聚合酶链反应（PCR）的筛查。
CYP11B1活性未改变，但子痫前期患者中四氢（TH） - Aldo平均排泄量降低了3.9倍，表明CYP11B2活性降低。因此，子痫前期患者中（TH - 11 - 脱氢皮质酮[A] + TH - 皮质酮[B] + 5α - THB）与（TH - 可的松 + TH - 皮质醇[F] + 5α - THF）的比值以及18 - OH - THA与THAldo的比值分别增加了2.6倍和15.2倍，表明由于甲基氧化酶（MO）活性降低导致醛固酮合成减少。与子痫前期患者相比，正常妊娠女性中携带CYP11B2突变的比例较低（P < 0.05）。检测到8种多态性，其中2种是非氨基酸保守性的。其中，先前发现会损害MO活性的V386A突变仅在子痫前期患者中观察到（0%对17%；P < 0.05）。
醛固酮合成中MO步骤受损导致的醛固酮缺乏有利于细胞外液容量减少，并可能解释胎盘灌注不足风险增加及子痫前期连续发展的原因。子痫前期母亲中仅存在V386A突变可能确定了一个在孕期发生子痫前期风险增加的亚组。
